During the funding period we identified, examined and collected blood samples from 1150 individuals from 301 families of Caribbean Hispanic origin with familial Alzheimer disease, and are currently processing data already collected in another 77 families (281 individuals). We have completed a first-stage genome-wide scan consisting of 340 markers in the first 98 families identified, and we have successfully applied to Center for Medical Genetics at the Marshfield Medical Research Foundation to have the remaining families genotyped. In our first-stage genome scan, we observed several peaks with parametric two-point lod scores exceeding 1.0, but the highest lod scores were 3.15 at chromosome 18q21 and 2.00 at chromosome 12p 12. Using non-parametric multipoint analyses we identified several NPL scores with p< 0.05, but the highest NPL scores were on chromosome 18q21 (p=0.003) and 10q26 (p=0.007). We will present encouraging new data from the initial fine mapping in these regions in the progress report. During the next 5 years, we will perform studies to fine map these chromosomal regions and to identify the corresponding genes. Our hypothesis remains that one or more susceptibility genes, in addition to APOE, increase the risk of Alzheimer's disease among Caribbean Hispanics. The overall goal of this project is to identify variations in genes among Caribbean Hispanics that increase the risk of developing Alzheimer's disease. First, we propose to expand fine mapping in the Knowles and Tycko laboratories at Columbia University and the St George-Hyslop laboratory at the University of Toronto of genomic regions with strongest support for linkage on chromosomes 18, 10, 12 and 21 from our initial genome scan. Second, we will conduct genetic linkage analyses using the new marker data provided to us by The Center for Medical Genetics at the Marshfield Medical Research Foundation using the entire set of families. By contrasting and comparing the results of the 1st and 2"d scans we will improve map resolution and prioritize subsequent fine mapping efforts. We will follow-up the entire cohort of existing families to confirm diagnoses, assess disease progression, discuss autopsy permission, re-examine those at risk and extend phenotypes. We will collect clinical information and obtain blood to establish cell lines in an additional 300 Caribbean Hispanic families with Alzheimer's disease to augment fine mapping. We will confirm any putative candidate gene from the fine mapping efforts in the independent Caribbean Hispanic population sample in New York City. Further we will make cells lines and clinical information available to others through the National Cell Repository for Alzheimer's Disease.